MiR-21 regulates biological behavior through the PTEN/PI-3 K/Akt signaling pathway in human colorectal cancer cells

Xiong,Binghong; Cheng,Yong; Ma,Li; Zhang,Caiquan

doi:10.3892/ijo.2012.1707

MiR-21 regulates biological behavior through the PTEN/PI-3 K/Akt signaling pathway in human colorectal cancer cells

Authors:
- Binghong Xiong
- Yong Cheng
- Li Ma
- Caiquan Zhang
View Affiliations

Affiliations: Department of General Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China, Department of Internal Medicine, Chongqing Huaxi Hospital, Chongqing 400054, P.R. China
Published online on: November 20, 2012 https://doi.org/10.3892/ijo.2012.1707
Pages: 219-228

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of this study was to determine a role of microRNA-21 (miR-21) in colorectal cancer (CRC) and to elucidate the regulation of phosphatase and tensin homologue (PTEN) gene by miR-21. MiR-21 expression was investigated in 30 CRC samples and five CRC cell lines. In this study, we show that the expression of miR-21 was overexpressed in CRC compared with adenomas and normal tissues. Patients with poor differentiation, lymph node metastasis and advanced TNM stage showed significantly high expression of miR-21. Inhibition of miR-21 in the HCT116 cell line reduced cellular proliferation, migration and invasion, induced apoptosis and inhibited cell cycle progression. The PTEN protein levels in CRC tissues and cells had an inverse correlation with miR-21 expression. Anti-miR-21-transfected cells increased PTEN protein expression without changing the PTEN mRNA level and increased a luciferase-reporter activity. MiR-21 targets PTEN at the post-transcriptional level and regulates cell proliferation and invasion in CRC. It may serve as a novel therapeutic target in CRC.

View Figures

View References

1.	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2.	Zhang YL, Zhang ZS, Wu BP and Zhou DY: Early diagnosis for colorectal cancer in China. World J Gastroenterol. 8:21–25. 2002.
3.	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar
4.	Fearon ER and Vogelstein B: A genetic model for colorectal tumorigenesis. Cell. 61:759–767. 1990. View Article : Google Scholar : PubMed/NCBI
5.	Valencia-Sanchez MA, Liu J, Hannon GJ and Parker R: Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 20:515–524. 2006. View Article : Google Scholar : PubMed/NCBI
6.	Taylor DD and Gercel-Taylor C: MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancer. Gynecol Oncol. 110:13–21. 2008. View Article : Google Scholar : PubMed/NCBI
7.	Chim SS, Shing TK, Hung EC, et al: Detection and characterization of placental microRNAs in maternal plasma. Clin Chem. 54:482–490. 2008. View Article : Google Scholar : PubMed/NCBI
8.	Mayr C, Hemann MT and Bartel DP: Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science. 315:1576–1579. 2007. View Article : Google Scholar : PubMed/NCBI
9.	Giraldez AJ, Cinalli RM, Glasner ME, et al: MicroRNAs regulate brain morphogenesis in zebrafish. Science. 308:833–838. 2005. View Article : Google Scholar : PubMed/NCBI
10.	Chen CZ, Li L, Lodish Hf and Bartel DP: MicroRNAs modulate hematopoietic lineage differentiation. Science. 303:83–86. 2004. View Article : Google Scholar : PubMed/NCBI
11.	Hornstein E, Mansfield JH, Yekta S, et al: The microRNA miR-196 acts upstream of Hoxb8 and Shh in limb development. Nature. 438:671–674. 2005. View Article : Google Scholar : PubMed/NCBI
12.	Marson A, Levine SS, Cole MF, et al: Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell. 134:521–533. 2008. View Article : Google Scholar : PubMed/NCBI
13.	Kent OA and Mendell JT: A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene. 25:6188–6196. 2006. View Article : Google Scholar : PubMed/NCBI
14.	Cho WC: MicroRNAs in cancer -from research to therapy. Biochim Biophys Acta. 1805:209–217. 2010.PubMed/NCBI
15.	Cho WC: MicroRNAs: potential biomarkers for cancer diagnosis, prognosis and targets for therapy. Int J Biochem Cell Biol. 42:1273–8121. 2010. View Article : Google Scholar : PubMed/NCBI
16.	Volinia S, Calin GA, Liu CG, et al: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA. 103:2257–2261. 2006. View Article : Google Scholar : PubMed/NCBI
17.	Iorio MV, Ferracin M, Liu CG, et al: MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 65:7065–7070. 2005. View Article : Google Scholar : PubMed/NCBI
18.	Si ML, Zhu S, Wu H, Lu Z, Wu F and Mo YY: MiR-21-mediated tumor growth. Oncogene. 26:2799–2803. 2007. View Article : Google Scholar : PubMed/NCBI
19.	Lee EJ, Gusev Y, Jiang J, Nuovo GJ, et al: Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer. 120:1046–1054. 2007. View Article : Google Scholar : PubMed/NCBI
20.	Roldo C, Missiaglia E, Hagan JP, et al: Micro-RNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol. 24:4677–4684. 2006. View Article : Google Scholar : PubMed/NCBI
21.	Meng F, Henson R, Lang M, et al: Involvement of human micro-RNA in growth and response to chemotherapy in human cholangiocarcinoma cell lines. Gastroenterology. 130:2113–2129. 2006. View Article : Google Scholar : PubMed/NCBI
22.	Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST and Patel T: MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 133:647–658. 2007. View Article : Google Scholar : PubMed/NCBI
23.	Hiyoshi Y, Kamohara H, Karashima R, et al: MicroRNA-21 regulates the proliferation and invasion in esophageal squamous cell carcinoma. Clin Cancer Res. 15:1915–1922. 2009. View Article : Google Scholar : PubMed/NCBI
24.	Schetter AJ, Leung SY, Sohn JJ, et al: Micro-RNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA. 299:425–436. 2008. View Article : Google Scholar : PubMed/NCBI
25.	Chan JA, Krichevsky AM and Kosik KS: MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 65:6029–6033. 2005. View Article : Google Scholar : PubMed/NCBI
26.	Lui WO, Pourmand N, Patterson BK and Fire A: Patterns of known and novel small RNAs in human cervical cancer. Cancer Res. 67:6031–6043. 2007. View Article : Google Scholar : PubMed/NCBI
27.	Iorio MV, Visone R, Di Leva G, et al: MicroRNA signatures in human ovarian cancer. Cancer Res. 67:8699–8707. 2007. View Article : Google Scholar : PubMed/NCBI
28.	Fulci V, Chiaretti S, Goldoni M, et al: Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia. Blood. 109:4944–4951. 2007. View Article : Google Scholar : PubMed/NCBI
29.	Löffler D, Brocke-Heidrich K, Pfeifer G, et al: Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer. Blood. 110:1330–1333. 2007.PubMed/NCBI
30.	Ziyan W, Shuhua Y, Xiufang W and Xiaoyun L: MicroRNA-21 is involved in osteosarcoma cell invasion and migration. Med Oncol. 28:1469–1474. 2011. View Article : Google Scholar : PubMed/NCBI
31.	Zhang JG, Wang JJ, Zhao F, Liu Q, Jiang K and Yang GH: MicroRNA-21 (miR-21) represses tumor suppressor PTEN and promotes growth and invasion in non-small cell lung cancer (NSCLC). Clin Chim Acta. 411:846–852. 2010. View Article : Google Scholar : PubMed/NCBI
32.	Zhang BG, Li JF, Yu BQ, Zhu ZG, Liu BY and Yan M: MicroRNA-21 promotes tumor proliferation and invasion in gastric cancer by targeting PTEN. Oncol Rep. 278:1019–1026. 2012.PubMed/NCBI
33.	Asangani IA, Rasheed SA, Nikolova DA, et al: MicroRNA-21 (miR-21) posttranscriptionally down-regulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 27:2128–2136. 2008. View Article : Google Scholar : PubMed/NCBI
34.	Nagao Y, Hisaoka M, Matsuyama A, et al: Association of microRNA-21 expression with its targets, PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma. Mod Pathol. 25:112–121. 2012. View Article : Google Scholar : PubMed/NCBI
35.	Gabriely G, Wurdinger T, Kesari S, et al: MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators. Mol Cell Biol. 28:5369–5380. 2008. View Article : Google Scholar : PubMed/NCBI
36.	Zhang Z, Li Z, Gao C, et al: MiR-21 plays a pivotal role in gastric cancer pathogenesis and progression. Lab Invest. 88:1358–1366. 2008. View Article : Google Scholar : PubMed/NCBI
37.	Zhu S, Wu H, Wu F, Nie D, Sheng S and Mo YY: MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res. 18:350–359. 2008. View Article : Google Scholar : PubMed/NCBI
38.	Zhu S, Si ML, Wu H and Mo YY: MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem. 282:14328–14336. 2007. View Article : Google Scholar : PubMed/NCBI
39.	Papagiannakopoulos T, Shapiro A and Kosik KS: MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. Cancer Res. 68:8164–8172. 2008. View Article : Google Scholar : PubMed/NCBI
40.	Thum T, Gross C, Fiedler J, et al: MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signaling in fibroblasts. Nature. 456:980–984. 2008. View Article : Google Scholar : PubMed/NCBI
41.	Sayed D, Rane S, Lypowy J, et al: MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths. Mol Biol Cell. 19:3272–3282. 2008. View Article : Google Scholar : PubMed/NCBI
42.	Liu M, Tang Q, Qiu M, et al: MiR-21 targets the tumor suppressor RhoB and regulates proliferation, invasion and apoptosis in colorectal cancer cells. FEBS Lett. 585:2998–3005. 2011. View Article : Google Scholar : PubMed/NCBI
43.	Song B, Wang C, Liu J, et al: MicroRNA-21 regulates breast cancer invasion partly by targeting tissue inhibitor of metalloproteinase 3 expression. J Exp Clin Cancer Res. 29:292010. View Article : Google Scholar : PubMed/NCBI
44.	Selaru FM, Olaru AV, Kan T, et al: MicroRNA-21 is over-expressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3. Hepatology. 49:1595–1601. 2009. View Article : Google Scholar : PubMed/NCBI
45.	Chen C, Ridzon DA, Broomer AJ, et al: Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 33:e1792005. View Article : Google Scholar : PubMed/NCBI
46.	Slaby O, Svoboda M, Fabian P, et al: Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology. 72:397–402. 2007. View Article : Google Scholar : PubMed/NCBI
47.	Kulda V, Pesta M, Topolcan O, et al: Relevance of miR-21 and miR-143 expression in tissue samples of colorectal carcinoma and its liver metastases. Cancer Genet Cytogenet. 200:154–160. 2010. View Article : Google Scholar : PubMed/NCBI
48.	Fassan M, Pizzi M, Giacomelli L, et al: PDCD4 nuclear loss inversely correlates with miR-21 levels in colon carcinogenesis. Virchows Arch. 458:413–419. 2011. View Article : Google Scholar : PubMed/NCBI
49.	Liu K, Li G, Fan C, Zhou X, Wu B and Li J: Increased expression of microRNA-21 and its association with chemotherapeutic response in human colorectal cancer. J Int Med Res. 39:2288–2295. 2011. View Article : Google Scholar : PubMed/NCBI
50.	Drebber U, Lay M, Wedemeyer I, et al: Altered levels of the onco-microRNA 21 and the tumor-supressor microRNAs 143 and 145 in advanced rectal cancer indicate successful neoadjuvant chemoradiotherapy. Int J Oncol. 39:409–415. 2011.
51.	Chang KH, Miller N, Kheirelseid EA, et al: MicroRNA-21 and PDCD4 expression in colorectal cancer. Eur J Surg Oncol. 37:597–603. 2011. View Article : Google Scholar : PubMed/NCBI
52.	Shibuya H, Iinuma H, Shimada R, Horiuchi A and Watanabe T: Clinicopathological and prognostic value of microRNA-21 and microRNA-155 in colorectal cancer. Oncology. 79:313–320. 2010. View Article : Google Scholar : PubMed/NCBI
53.	Yamamichi N, Shimomura R, Inada K, et al: Locked nucleic acid in situ hybridization analysis of miR-21 expression during colorectal cancer development. Clin Cancer Res. 15:4009–4016. 2009. View Article : Google Scholar : PubMed/NCBI
54.	Wang P, Zou F, Zhang X, et al: MicroRNA-21 negatively regulates Cdc25A and cell cycle progression in colon cancer cells. Cancer Res. 69:8157–8165. 2009. View Article : Google Scholar : PubMed/NCBI
55.	Folini M, Gandellini P, Longoni N, et al: miR-21: an oncomir on strike in prostate cancer. Mol Cancer. 9:122010. View Article : Google Scholar : PubMed/NCBI
56.	Cheng AM, Byrom MW, Shelton J and Ford LP: Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res. 33:1290–1297. 2005. View Article : Google Scholar : PubMed/NCBI
57.	Jovanovic M and Hengartner MO: MiRNAs and apoptosis: RNAs to die for. Oncogene. 25:6176–6187. 2006. View Article : Google Scholar : PubMed/NCBI
58.	Li L, Ernsting BR, Wishart MJ, Lohse Dl and Dixon JE: A family of putative tumor suppressors is structurally and functionally conservedin humans and yeast. J Biol Chem. 272:29403–29406. 1997. View Article : Google Scholar : PubMed/NCBI
59.	Steck PA, Pershouse MA, Jasser SA, et al: Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 15:356–362. 1997. View Article : Google Scholar : PubMed/NCBI
60.	Li DM and Sun H: TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res. 57:2124–2129. 1997.
61.	Leslie NR and Downes CP: PTEN: the down side of PI 3-kinase signalling. Cell Signal. 14:285–295. 2002. View Article : Google Scholar : PubMed/NCBI
62.	Bader AG, Kang S, Zhao L and Vogt PK: Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer. 5:921–929. 2005. View Article : Google Scholar : PubMed/NCBI
63.	Hsu CP, Kao TY, Chang WL, Nieh S, Wang HL and Chung YC: Clinical significance of tumor suppressor PTEN in colorectal carcinoma. Eur J Surg Oncol. 37:140–147. 2011. View Article : Google Scholar : PubMed/NCBI
64.	Naguib A, Cooke JC, Happerfield L, et al: Alterations in PTEN and PIK3CA in colorectal cancers in the EPIC Norfolk study: associations with clinicopathological and dietary factors. BMC Cancer. 11:1232011. View Article : Google Scholar : PubMed/NCBI
65.	Wang ZX, Lu BB, Wang H, Cheng ZX and Yin YM: MicroRNA-21 modulates chemosensitivity of breast cancer cells to doxorubicin by targeting PTEN. Arch Med Res. 42:281–290. 2011. View Article : Google Scholar : PubMed/NCBI
66.	Hatley ME, Patrick DM, Garcia MR, et al: Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. Cancer Cell. 18:282–293. 2010. View Article : Google Scholar : PubMed/NCBI